1. Field of the Invention
The present invention relates to increasing growth hormone secretion and/or the biologic effects of growth hormone.
2. Discussion of the Background
The therapeutic administration of hormones--substances that act at sites distant from the location of release--has heretofore been subject to the technical limitations of pharmacology. In general, the pharmacological administration of hormones has meant virtually instant introduction of a large dose of an active agent. This is clearly contrary to the physiological nature of release which consists of small amounts released as required by a particular organism.
The dichotomy between pharmacology and physiology is commonly noted in insulin use. Normal subjects release insulin as needed. High amounts may be released when food is eaten, but chronic low levels remain available in times of reduced but not negligible demand. Diabetic subjects receive an approximated insulin dosage in about 1 to 3 injections daily with only minimal accommodation possible for moment to moment insulin demands or insulin by pump supplemented with bolus injections.
A similar dichotomy is found with growth hormone. Growth hormone releasing factor is a hormone produced in the brain which stimulates the release of growth hormone from the pituitary. It has previously been shown in that the administration of growth hormone releasing factor stimulates growth hormone secretion from the pituitary of multiple different species from fish to man. The structure of human growth hormone releasing factor has previously been described and is made up of 40 or 44 amino acids (Rivier, J; Spiess, J; Thorner, M; Vale, W; Nature, 1982, 300, 276-278; Spiess, J; Rivier, J; Thorner, M; Vale, M; Biochemistry, 1982, 24, 6037-6040, and Guillemin, R; Brazeau, P; Bohlen, P; Esch, F; Ling, N; Science, 1982, 218, 585-587). Analogs of the peptide ranging from 29 amino acids or longer have also been shown to stimulate growth hormone secretion.
Growth hormone, like insulin, is also regulated by an inhibitory hormone produced by the hypothalamus called somatostatin. Studies in animals have suggested that growth hormone releasing factor desensitizes those cells which secreted growth hormone in response to the growth hormone releasing factor. Pharmaceutically administered Growth Releasing Factor has heretofore been believed to be effective only when administered in a discontinuous manner and over a length of time. As a matter of fact, one study on the normal rat indicates that pulsatile growth hormone releasing factor administration accelerates growth, while continuous administration of growth hormone releasing factor does not (Clark R, G; Nature, 1985, 314, 281-283). It has thus been considered necessary to give growth hormone releasing factor by pulsatile administration. Patients suffering from growth hormone deficiency have heretofore been given inconvenient and time consuming periodic injections of growth hormone releasing factor or growth hormone; typically by 2 to 3 times weekly injections for growth hormone or repeated injections per day for growth hormone releasing factor or pump pulsitile administration.
Accordingly, the existing methods of administering growth hormone releasing factor suffer the disadvantage of difficulty of patient compliance with the treatment, as well as pain or dangers associated with multiple administrations. Children especially do not like the treatment and are difficult to keep on administration schedule.